Abstract 044: Knocking Out Sodium Glucose-Linked Transporter 5 Prevents Fructose-Induced Salt-Sensitive Hypertension

Abstract

We showed: 1) a 20% fructose high-salt (3.7% NaCl; FHS) but not a 20% glucose high-salt diet increases systolic blood pressure (SBP) in a sex independent manner; 2) on normal salt, 20% fructose augments the ability of angiotensin II (Ang-II) to increase proximal tubule superoxide (O 2 - ); and 3) rat proximal tubule brush borders express sodium glucose-linked transporters (SGLT) 4 and SGLT5, which transport fructose. However, whether FHS enhances Ang II-stimulated proximal tubule O 2 - , its role in FISSH and the roles of SGLT4 and 5 are unknown. We hypothesized that fructose transport mediated by SGLT5 but not SGLT4 is required for FHS to enhance Ang II-stimulated proximal tubule O 2 - in males and females, and this is required for fructose-induced salt-sensitive hypertension (FISSH). We measured SBP in wild-type, SGLT4 knockout, and SGLT5 knockout male and female rats on a Sprague Dawley background fed FHS for 7 days. We also measured basal and Ang II-stimulated (37 nM) O 2 - in proximal tubule suspensions from these rats using the lucigenin assay. FHS increased SBP in wild type male rats 11 ± 2 mmHg (from 131 ± 4 to 142 ± 5 mmHg; n = 5, p < 0.01) and in female rats by 21 ± 5 mmHg (from 114 ± 4 to 130 ± 3 mmHg; n = 8; p < 0.01), not significantly different from males. FHS increased SBP in SGLT4 males by 22 ± 3 mmHg (from 126 ± 5 to 149 ± 6 mmHg; n = 8, p < 0.01) and in females 21 ± 5 mmHg (from 126 ± 3 to 138 ± 2 mmHg; n = 8; p < 0.01), not significantly different from males. In SGLT5 males SBP was 128 ± 6 on day 0 and 129 ± 8 mmHg on day 7 (n = 7). In SGLT5 females SBP was 114 ± 4 on day 0 and 117 ± 5 mmHg on day 7 (n = 7). Ang-II increased O 2 - by 11 ± 3 relative light units (RLU)/μg/s from 53 ± 9 to 64 ± 8 RLU/μg/s (n = 11, p < 0.01) in tubules from wild type males fed FHS for 7 days and by 10±3 RLU (n = 5; p < 0.02) in females fed FHS for 7 days. Ang-II increased O 2 - by 8 ± 2 RLU/μg/s in proximal tubules from FHS-fed SGLT4 males (n = 6, p < 0.02) and by 8 ± 2 in FHS-fed females (n = 6, p < 0.01). Ang-II did not significantly stimulate O 2 - in proximal tubules from FHS-fed SGTL5 male or female rats (Δ 3±7 and 0±3 RLU/μg/s, n = 5 and 3, respectively). We conclude that transport by SGLT 5 but not SGLT4 is required for FHS to augment Ang II-stimulated proximal tubule O 2 - in males and females, and that the increase in proximal tubule oxidative stress is required for FISSH.